Chronic psychic stress can cause metabolic

syndrome through mild hypercapnia

ANDRAS SIKTER1
1
Municipal Clinic of Szentendre, Internal Medicine, Szentendre Kanonok u. 1., Hungary

The author presents a new psychosomatic stress model. All the elements of the hypothesis
are well known but, in this context, are published first. The following are the most critical
aspects of the recommended chronic stress model. 1/ Stress contains both sympathetic and
parasympathetic elements, but the latter predominate. 2/ The mediator of stress is carbon
dioxide, the substance that can turn the psyche into soma. 3/ In humans, chronic stress is
mainly social; people cause it to each other. Chronic social stress is created frequently due
to deviations in civilisation, education and tolerance. 4/ The freeze response (or freezing
behaviour) plays a subordinate role in the animal world; it lasts mainly for a maximum
of minutes, while in humans, it dominates and can continue for decades. 5/ The decisive
step of freeze is apnea, hypopnea, which occurs due to aversive psychological effects.
After a more extended existence, mild chronic respiratory acidosis develops and most
often appears in the clinical form of obstructive sleep apnea. 6/ Chronic hypercapnia can
shape the metabolism into metabolic syndrome. 7/ After that, various cardiovascular and
metabolic complications (hypertension, atherosclerosis, type 2 diabetes, depression) may
develop - partly due to genetic and lifestyle reasons.
(Neuropsychopharmacol Hung 2022; 24(3): 126–133)

Keywords: freeze response (=freezing behaviour), chronic stress, carbon dioxide, metabolic
syndrome, avoidance, human behaviour

126 NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM

Chronic psychic stress can cause metabolic syndrome through low-grade hypercapnia
INTRODUCTION
Despite extensive research, it remains unclear whether
metabolic syndrome has a single cause or it is from
multiple underlying risk factors (Wolk and Somers,
2007). The role of stress, environment, behaviour and
genetics is also unclear in the pathophysiology of
metabolic syndrome. Is there a connection between
OSA and metabolic syndrome or not (Wolk and
Somers, 2007)? The author of this review intends
to shed light on these questions by arranging the
literature data in a logical order.
Cannon's fight-or-flight response stress theory is
based purely on sympathetic neuro-humoral reactions
(Cannon, 1929). It may be because animal stress-
related parasympathetic responses have remained
hidden for a long time. Barlow suggested an adaptive
fear-alarm model. This freeze reaction could develop
in threatening situations when the momentary fright
elicits a parasympathetic pathway (Barlow, 2002). The
literature calls hypervigilance when the prey assesses
the threat with a cool head (Bracha, 2004). This period
mostly lasts for a few seconds to minutes in animals
(Barlow, 2002).
The main threat to humans today is no longer animal
predators but fellow human beings. The individual must
adapt to the communities, and fit into the hierarchy of
power, as there is nowhere to flee, so in most cases, the
consequence will be compromised to live a relatively
good life by following the rules. Cannon's fight-or-flight
response theory deservedly conquered 20th-century
stress researchers, but the result was that all stress
damage was written at the expense of the sympathetic
nervous system and adrenergic mechanisms (Borchard,
2001). Over time, it had to be seen that probably
not adrenaline but “chronic stress” causes athero-
sclerosis, whatever it means (Vitaliano et al., 2002).
Stress, psychosocial distress, and pathophysiology
of psychosomatic diseases are among the most
researched areas of medicine. The Achilles' point
of the question is what can be the mediator and
pathophysiologic pathway of psychosomatic processes.
There is a broad consensus that psychosocial stress
correlates most with cortisol levels; however, the
authors suggest that the mediator and mediating
mechanism are unresolved (Ruesch, 1961; Lockhart
et al., 2011). Few believe that a parasympathetic
pathway could play a significant/determinant role
in the pathophysiology of psychosomatic diseases.
However, the human aspects of the parasympathetic
freeze of the stress response have only been intensively
researched recently (Roelofs, 2017).
NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
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The author et al. previously suggested carbon
dioxide as a potential mediator of psychic and
psychosomatic processes (Sikter et al., 2009).
Alterations of emotion change the breathing pattern
and the momentary pCO2 level (Sikter et al., 2009).
On the other hand, the changing level of pCO2 affects
mental and physical functioning and arousal - in a
word, carbon dioxide is an essential link between
psyché and soma.
CARBON DIOXIDE CAN MEDIATE BOTH
EXTEROCEPTIVE AND INTEROCEPTIVE
STRESS
Amygdala is an almond-shaped cluster of nuclei of
the mammalian brain thought for processing fearful
and threatening stimuli, including detecting threats
and activating fear-related behaviours (Baxter and
Croxson, 2012). The amygdala not only mediates
fear and anxiety (Davis et al., 2010), but it also has a
chemosensory role (Ziemann et al., 2009).
The intention to avoid imminent suffocation is an
elemental stress response that has already appeared
in animals such as Caenorhabditis elegans and Dro-
sophila melanogaster (Bretcher et al., 2011; Suh et
al., 2004). Organisms detect elevation in CO2 levels
with a high degree of accuracy at many points of their
body. In mammals, the amygdala collects information
from peripheral and central CO2 chemoreceptors.
Carbon dioxide level elevation is a much more
sensitive indicator of imminent suffocation than
the O2 decrease (Feinstein et al., 2022). Feinstein
distinguishes between interoceptive and exteroceptive
threats (Feinstein et al., 2022). The interoceptive one is
an interior CO2 elevation, which immediately causes
a suffocation alarm without touching the amygdala.
It can be mimicked with concentrated (35%) CO2
inhalation. In the case of exteroceptive notice, the
information comes through various signalling
systems and touches the amygdala, causing apnea in
the brainstem. The consequent pCO2 level elevation
causes a feeling of threat through the amygdala.
The role of carbon dioxide is underestimated in
stress and psychosomatic disorders. This review
points out that CO2 itself is the mediator of the stress
reaction in both exteroceptive and interoceptive stress.
CO2 gas has excellent solubility in both body water
and lipids, so it can penetrate through membranes
without hindrance and act its effect in neurons and
somatic cells. CO2 is suitable for mediating negative
emotions (fear, anxiety, suffocation alarm) as changes
in pCO2 levels occur rapidly. In this way, carbon
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dioxide can link the psyche and soma, a device that
mediates physiological functions but can also cause
diseases; it is a mediator.
Not only the elevated pCO2 can cause fear and
anxiety, but the actual spiritual status also influences
the respiratory process (we start breathing rarely,
frequently, and irregularly), causing pCO2 and pH
alterations in the organism (Sikter et al., 2009). On
the other hand, the actual cytosolic pH of neurons is
one of the primary modifiers of Ca2+ conductance in
the membranes, thereby fundamentally changing the
working of the neurons and nervous system (Sikter
et al., 2009).
AVOIDANCE COMES FROM THE FREEZE
Cannon did not notice that a fight-or-flight stress
response is usually preceded by a short freeze response
period, which Barlow first studied in detail (Barlow,
2002). However, the details of the freeze response are
mostly unexplored in human cases (Roelofs, 2017).
Freeze is an essential introductory part of the defence
cascade that activates parasympathetic or sympathetic
pathways according to need. In animals, usually, it
continues with a fight-or-flight stress response
(Kozlowska et al., 2015).
The emergency information travels to the amygdala
and the brainstem, which can induce apnea; the
developed hypercapnia triggers fear and other
negative emotions (Feinstein et al., 2022). Meanwhile,
motility decreases through a vagotonic reflex, it lasts
for seconds or minutes (Barlow, 2002). During the
freeze, the animal evaluates the size of the danger
and things to do; this stress response promotes a
cool-headed prey's decision: “stop, look, and watch”
(Bracha, 2004).
The parasympathetic condition causes a slowdown
in heart rate, although there are signs of a sympathetic
tone. Freeze is a universal fear response, which
varies from species to species and has a pronounced
parasympathetic dominance in humans (Hermans
et al., 2013).
The avoidance definition by the American Psycho-
logical Association (APA) is “any act or series of
actions that enable an individual to avoid or anticipate
unpleasant or painful situations, stimuli, or events,
including conditioned aversive stimuli.” In practice,
freeze is first and foremost for avoiding the threat
(Rösler and Garne, 2019). Immobility and hyper-
vigilance increase the chances of avoiding and
surviving an attack. Increasing carbon dioxide levels
can be considered the ancient mediator of negative
128
Andras Sikter
emotions and avoidance. Research has studied many
natural, artificial, inescapable, and escapable forms
of carbon dioxide expositions. Most species try to
avoid it more or less successfully (Arméndola and
Weary, 2020).
We must distinguish between the stresses
threatening animals and humans and how to avoid
them. While acute fight-or-flight stress response
predominates in wild animals, freezing behaviour
is more prevalent in humans. Terminologically
and considering its metabolic effects, freeze is a
parasympathetic phenomenon (Hermans et al.,
2013). Both momentary current pCO2 levels and
intracellular pH fundamentally affect the functioning
of the body’s cells, which changes mimic the operation
of the autonomic nervous system. The hypercapnia
can mimic the parasympathetic tone and synergist
with it. These facts are mostly overlooked (Sikter et
al., 2017a, 2017b; Sikter, 2018). The body strives to
achieve a balance in sympathetic-parasympathetic
tone, so several sympathetic phenomena and humoral
responses can occur during chronic human stress,
and these often exacerbate the outcomes, leading
to diseases of civilisation (Sikter et al., 2009, 2017a,
2017b; Sikter and Sonne, 2021a).
CHRONIC STRESS, SOCIAL STRESS,
THE ROLE OF HUMAN BEHAVIOUR
If stress is not resolved in the short term, is prolonged
or recurs, we are talking about chronic stress. Through
violence against nature, humans have created a model
with global warming - an increased concentration of
CO2 in living waters and air - in which researchers can
study the consequences of chronic stress. Fish can be
used for this stress model in a simple way, which is
remarkable in several respects. Fish cannot avoid the
rise in CO2 in their body as it is ubiquitous.
Incorporating higher CO2 mimics interoceptive
stress, drawing attention to the danger of real
environmental stress (Hermann, 2018). On the other
hand, the rise in CO2 levels seems not to be one of
the threatening dangers but the mediator of chronic
stress itself. Third, threat modelling has also been
carried out at the cellular level in fish (Hermans
et al., 2013). The exteroceptive and interoceptive
stressors became the same: elevated CO2 levels in
the body's cells (Feinstein et al., 2022). According
to the author's hypothesis of the present article,
social stress in humans will also increase pCO2
levels, which is the stress mediator through freeze
response (see later).
NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
Chronic psychic stress can cause metabolic syndrome through low-grade hypercapnia
In the wild animal kingdom, a freeze response
is rarely followed by tonic immobility because it is
usually not successful against the predator (Bracha,
2004). On the other hand, it becomes increasingly
clear that freeze can be one of the primary weapons
of humans in the defence against social threats. The
individual often and effectively defends oneself in
emergencies in a freeze-like way because a fight-
or-flight response is mostly not allowed morally by
humans (Noordewier et al., 2020).
Roelofs showed that a person could respond to a
social threat with a freeze response (Roelofs et al.,
2010). However, the neurobiological mechanism
of freeze action is similar in animals and humans.
Humans, as social beings, show significant
differences in behaviour from animals (Roelofs,
2017). According to Roelofs, freezing in humans
is not a passive state but a “parasympathetic brake
on the motor system”, which allows them to calmly
consider the situation and thus successfully avoid
the threatening position.
Wheaton distinguished seven problems that
suggest chronic stress, but it can develop in many
other ways (Wheaton, 1997). The severity of distress
depends primarily on how deep a mark a psychic
stressor leaves on the individual's soul. So we should
distinguish between simple discomfort feeling and
shame, as well as between all the psychic stressors
that provoke helplessness and repressed anger. Several
other psychological mechanisms can play a role, such
as humiliation, helplessness, hopelessness, and fee-
ling of insecurity (Bradley et al., 2001). Inhibited
anger (together with fear) can indeed lead to somatic
diseases (Scuteri et al., 2001).
It seems likely that salt-sensitive hypertension,
which is well known to be much more common
among Afro-Americans, does not develop primarily
on genetic grounds but through a psychosomatic
mechanism due to suffering from racism, as
Anderson’s publication suggests (Anderson et al.,
2001). (If this statement is confirmed, it would be
a considerable step ahead in the pathophysiology.)
In the short term, parasympathicotonia may be
beneficial because it helps conserve and manage
resources. Although, it is exceptionally detrimental
to both psychiatric adaptation and its long-term
metabolic consequences. Learned behaviours
(tolerance) and education on civilised behaviour
make chronic stress a universal phenomenon. Human
education may generalise freezing behaviour; that is, it
NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
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cools the manifestations of the fight-or-flight response,
and a freezing-like behaviour becomes the sine qua
non of civilian behaviour. No primate community
would tolerate such high population levels of animals
as humans. But it comes at a price: chronic social
stress and distress. Many social and psychological
factors hamper social coexistence. There are many
degrees of difficulty, such as aversion, fear, anxiety
and social defeat, which the individual wants to avoid
naturally, but this is often unsolvable for subsistence
and integration into a community. So most people
give themselves up spiritually and put up with it. Age
also plays a significant role; the question is whether
mental factors (such as “wisdom” or opportunism)
or the age-related slowing of metabolism play a more
critical role. (In the latter, as a part of The Second
Law of Thermodynamics, is also suspect (Sikter et
al., 2017b).
Ethologists and behaviour researchers have long
modelled the social defeat by caged rodents. It was
shown in caged rats that persistent, repeated psychic
or physical abuse can lead to freezing behaviour. The
induced bradycardia and bradypnoea (hypercapnia)
lasted for at least ten days (Brouillard et al., 2016).
Although the stress had disappeared, half of the rats
still had bradypnoea for weeks. Hypoventilation often
becomes habitual and persists even after repeated or
chronic stress is over.
The individual consciously (or subconsciously)
accepts that he has no choice but to give up a part of
the ego, which triggers a freeze response, one element
of which is hypoventilation, which leads to the first
materialised factor in the psychic stress - to the
elevated pCO2 level. If the stress lasts days to weeks,
the hypercapnic acidosis becomes “compensated.”
And then, hypoventilation may become permanent
or fragmented and repeated; it has more forms than
OSA, OHS or COPD. OSA can be the most common
manifestation of chronic hypercapnia in which
psychosomatic mechanisms occur. After prolonged
existence, it can develop somatic diseases (Sikter et
al., 2017b). At the societal level, avoidance often does
not work, which is why the mean pCO2 levels and the
intracellular HCO3- /Cl- levels increase (Sikter and
Sonne, 2021a, 2021b).
Chronic stress occurs because the body cannot
avoid its oldest enemy, the pCO2 level elevation.
While the freeze response in animals - except for
tonic immobility – lasts a maximum of minutes, in
humans, a freeze-like state can continue for decades
(Sikter et al., 2017b).
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MILD CARBON DIOXIDE ELEVATION CAUSED
BY CHRONIC STRESS COULD TRIGGER
METABOLIC SYNDROME
It was repeatedly suggested that the metabolic
syndrome would be of psychosomatic origin, but
the pathway leading to it has not been found so far
(Ghike, 2016). Others think the same about OSA
(Vitaliano et al., 2002; Bergmann et al., 2014). Many
have connected OSA with metabolic syndrome as
there is a significant correlation between the two
syndromes (Wolk and Somers, 2007; Lam et al.,
2012; Gaines et al., 2018; Chan et al., 2019; Ryan et
al., 2020). The carbon dioxide elevation could be
their common denominator. However, the carbon
dioxide level elevation is not included in a list of a
recently published systematic review of physiological
biomarkers of chronic stress (Noushad et al., 2021).
Well, recently, it has been suspected that intermittent
hypercapnia may be a trigger for metabolic syndrome
in OSA (Ryan et al., 2020)! The difference between
the physiological and pathogenic levels of pCO2 is
relatively small, meaning that carbon dioxide would
have a much stronger effect than previously thought
and that the levels hitherto considered normal
are questionable (Sikter and Sonne, 2021a). OSA
correlates strongly with metabolic syndrome among
the three major hypercapnic diseases (OSA, OHS,
COPD). Because hypoxia and hypercapnia interact
strongly, they have a synergistic effect (Berger et
al., 2000; Ryan et al., 2020), and hypoxic periods
enhance CO2 retention in tissues (Berger et al., 2000).
Although in OSA, the mean pCO2 levels are usually
slightly above normal (Eskandari et al., 2017).
Carbon dioxide has several strong effects, such
as on intracellular pH and, through this, on the
rate of metabolism, the immune system, and the
endothelial cells of the lung alveoli (Relman, 1972;
Zappulla, 2008; Curley and Laffey, 2014). It has
been known for some time from experiments on
primitive animal organisms that an increase in the
level of carbon dioxide per se can alter the expression
of specific genes and thus cause a metabolic change
in, for example, carbohydrate or fat metabolism or
immunity (Taylor and Cummins, 2011). Metabolism
modification occurs by transcribing specific genes
(Cormac and Taylor, 2011). A microarray technique
study analyzed gene expression in human epithelial
cells. They found that hypercapnia downregulated
the expression of 183 genes and upregulated 126
(Casalino-Masuda et al., 2018). Among these, ma-
jor gene clusters linked to lipid metabolism were
130
Andras Sikter
predominantly upregulated. These new data show
that CO2 can trigger cholesterol and lipid biosynthesis.
The elevated CO2 levels can alter gene expression and
activate signalling pathways, affecting cellular and
tissue functions (Shigemura et al., 2020). Based on the
above, we are talking about changes of phenotype, that
is, increased or decreased function of specific genes,
the genome remains unchanged. The question is, are
these changes partially or entirely reversible or not?
In fish, it has been shown that elevated chronic CO2
exposure alters lipid and triglyceride metabolism like
humans; the similarity is hardly coincidental; these
genes probably have already appeared at a lower level
of phylogeny (Hermann, 2018).
CARBON DIOXIDE TOLERANCE
– INDIVIDUAL DIFFERENCES IN STRESS
RESPONSIVENESS
Exposure to elevated CO2 can have marked effects
on certain gene expressions controlling metabolism,
fertility, and immunity (Cummins et al., 2020). CO2
exposure has a strong and specific effect on lipid
and triglyceride metabolism. It changes the body
cells' functioning to such a degree and direction
that mild chronic hypercapnia also could cause
metabolic syndrome (Sikter 2020; Sikter and Sonne,
2021a). In this way, the metabolic syndrome and
its complications would have a psychosomatic
origin (Vitaliano et al., 2002). Based on the above,
it is likely that carbon dioxide level elevation plays
a significant role in chronic (social, psychic) stress
and a determining role in the pathophysiology of
psychosomatic diseases. Nevertheless, the details have
yet to be revealed, as the degree of effective pCO2
elevation shows a significant deviation in different
individuals, so it should be assumed that individual
sensitivity and responsiveness play a crucial role
(Lovallo and Gerin, 2003).
The fine-tuning of CO2 chemosensation is a crucial
adaptive response to controlling acid-base balance
in tissues (Cummins et al., 2020). In psychiatric
diseases, it is known that CO2 sensitivity ranges
widely; the highest CO2 sensitivity was observed in
panic disorder, while the lowest was in depression
(Freire et al., 2010; Sikter et al., 2017b).
There must also be a reduced CO2 sensitivity,
which is the opposite of CO2 hypersensitivity.
Both conditions have a prominent role in psychic,
functional and psychosomatic disorders. While
CO2 hypersensitivity is relatively well explored in
connection with anxiety and panic disorders, the
NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
Chronic psychic stress can cause metabolic syndrome through low-grade hypercapnia
knowledge about the importance of reduced CO2
sensitivity is severely lacking. In addition to psychic
reactivity and emotional responsiveness, other factors
can also influence the body's respiratory response
to an increase in CO2 levels. Due to its importance,
the control of the pCO2 level is “over-insured”. For
example, many hormones also regulate pCO2 and pH
levels - this crosstalking can result in dysregulation
(Sikter et al., 2017a; 2017b; Cummins et al., 2020).
There is an unexpected pathophysiological effect
among the harms of cigarette smoking; it can be
explained by reduced CO2 sensitivity (Dunn et al.,
1982). The pathophysiology described above would
largely explain why sudden infant death syndrome
(SIDS) occurs due to mothers' smoking during
pregnancy (Ali et al., 2016). Furthermore, it also
explains why CO2 hypersensitivity develops after
smoking withdrawal, what is the psychic benefit
of tobacco, and the mental hindrance of quitting
(Abrams et al., 2011). Moreover, it is also explained
that reduced respiratory CO2 sensitivity may be the
common root of the metabolic syndrome and the
harms of smoke abuse, as smoking is associated with
similarly serious cardiovascular risks as metabolic
syndrome (Erhardt, 2009). Because of its importance,
the impact of CO2 on metabolism, gene expression
and psychosomatic mechanisms has begun to be
highly intensive research. Despite this, studies are
still only at the beginning.
LIST OF ABBREVIATIONS
CO2: carbon dioxide
COPD: chronic obstructive pulmonary disease
O2: oxygen
OHS: obesity hypoventilation syndrome
OSA: obstructive sleep apnea
pCO2: partial pressure of carbon dioxide
Corresponding author: Andras Sikter
Municipal Clinic of Szentendre, Internal Medicine,
Szentendre Kanonok u. 1., Hungary
E-mail: andrassikter3@gmail.com
NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
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NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM
Chronic psychic stress can cause metabolic syndrome through low-grade hypercapnia REVIEW

A krónikus pszichés stressz kisfokú

hiperkapnia révén metabolikus szindrómát
okozhat

A szerző egy új pszichoszomatikus stresszmodellt mutat be. A hipotézis minden eleme

jól ismert, de ebben az összefüggésben először publikálják. Az alábbiakban a javasolt
krónikus stressz modell legkritikusabb szempontjait mutatjuk be. 1/ A stressz szimpa-
tikus és paraszimpatikus elemeket egyaránt tartalmaz, de az utóbbiak vannak túlsúly-
ban. 2/ A stressz mediátora a széndioxid, az az anyag, amely képes „materializálni” a lelki
változást. 3/ Emberben a krónikus stressz főként szociális jellegű; az emberek okozzák
egymásnak. A krónikus szociális stressz gyakran a civilizáció, az oktatás és a tolerancia
devianciái miatt jön létre. 4/ A fagyási reakció (freeze) az állatvilágban alárendelt szerepet
játszik, és általában legfeljebb percekig tart, míg az embernél domináns és évtizedekig
folytatódhat. 5/ A freeze döntő következménye az apnoé, hipopnoé, amely averzív pszi-
chés hatások miatt következik be. Hosszabb fennállás után kisfokú krónikus légúti acidózis
alakul ki, amely leggyakrabban obstruktív alvási apnoe klinikai formájában jelenik meg.
6/ A krónikus kisfokú hiperkapnia metabolikus szindróma irányában alakíthatja át az anyag-
cserét. 7/ Ezt követően különböző kardiovaszkuláris és anyagcsere-szövődmények (magas
vérnyomás, érelmeszesedés, 2-es típusú cukorbetegség, depresszió stb.) alakulhatnak ki
– részben genetikai és életmódbeli okok miatt.

Kulcsszavak: fagyasztási reakció (freeze), krónikus stressz, széndioxid, metabolikus szind-

róma, elkerülés, emberi viselkedés.

NEUROPSYCHOPHARMACOLOGIA HUNGARICA 2022. XXIV. ÉVF. 3. SZÁM 133